Abstract

Overexpression and activation of HER (human epidermal growth factor receptor) family members have been reported in a wide range of epithelial tumours. Although several monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs) specific for the HER members have been approved for the treatment of patients with a wide range of tumours, none has yet been approved for the treatment of patients with ovarian cancer. In some studies, the co-expression of other growth factor receptors (e.g. c-MET), the presence of cancer stem cells (CSCs) have been associated with resistance to therapy with the HER inhibitors. The aim of the present study was to determine the expression level and prognostic significance of the EGFR, HER-2, HER-4 and EGFRvIII, as well as c-MET, CD44 and cell proliferation marker Ki67 in 60 patients with FIGO stage III and IV ovarian cancer. The expression levels of these markers were determined, at different cut off values, using immunohistochemistry (IHC), and their associations with the overall survival and disease free survival were evaluated using Chi-squared and Kaplan-Meier survival curves and log-rank test as well as the univariate Cox-regression analysis. At cut off values of >5% of tumour cells with positive immunostaining, 62%, 93%, 45%, 3%, 21%, 48%, and 95%, of the cases were positive for EGFR, HER-2, HER-4, EGFRvIII, c-MET, CD44, Ki67 respectively and 28% were positive for the co-expression of EGFR/HER-2/HER-4. The cellular location of immunostaining was membranous for EGFR, HER-2, c-MET and CD44 and was present in 33%, 10%, 3% and 50% of the cases examined respectively. In univariate analysis, the expression of EGFR at cut-off values of >50% (HR, 3.57; 95% CI, 1.07 to 11.85; P= <0.0001) and CD44 with 3+ intensity at cut-off values >5 % (HR, 8.20; 95% CI, 2.02 to 33.2; P= <0.0001) were associated with poorer overall survival. In contrast, the positive immunostaining of Ki67 at cut-off value >5% of tumour cells, was associated with better overall survival (HR, 0.13; 95% CI, 0.02 to 0.73; P= 0.021 respectively). In addition, at cut-off value of >5% of tumour cells with positive immunostaining, EGFR expression (HR, 2.83; 95% CI 1.18 to 6.77; P = 0.019) and >10% (HR, 2.40; 95% CI 1.07 to 5.37; P= 0.032 ), as well as the co-expression of EGFR/HER-2 (HR, 2.83; 95% CI 1.18 to 6.77; P= 0.019), EGFR/c-MET (HR, 3.05; 95% CI 1.2 to 7.75; P= 0.019) and EGFR/Ki67 (HR, 2.83; 95% CI 1.18 to 6.77; P= 0.019) were all associated with poorer disease free survival in these patients. Our results suggest that co-expression of EGFR\HER-2\HER4 is common in patients with Stages III and IV ovarian cancers and support the need for investigations on the therapeutic potential of various forms of pan-HER inhibitors in such patients.